The Transgenic Animal Model Core produces transgenic mice and gene targeted ("knockout") mice from embryonic stem (ES) cells carrying targeted genetic alterations. Transgenic mice are used in many ways, including the study of tissue specific gene expression, production of animal models of human disease, and testing efficacy of gene constructs for gene therapy. ES cell technology is used to establish animal models of recessive genetic disease and to characterize functional effects of gene loss and subtle changes in genes. ES cell technology is used to establish animal models of recessive genetic disease and to characterize functional effects of gene loss and subtle changes in genes. Other services provided include mouse embryo cryopreservation and recovery, derivation of pathogen free mice, and consultation. The Core maintains specialized reagents for transgenic and gene targeting research. The Core's specialized equipment is used to support the research efforts of multiple investigators who otherwise lack access to such equipment. The availability of a transgenic Core on site obviates the need for individual researchers to purchase costly equipment and invest personnel time in lengthy training in micromanipulation techniques, which would be technically and financially impossible for most investigators. Consultation on all aspects of transgenic and ES cell research is provided, from the design of DNA constructs to mouse husbandry. Production of Transgenic Mice: We deliver an average of ten transgenic founder mice and guarantee that at least three founders will be produced for each DNA construct submitted to the Core. Production of Gene Targeted ES Cells: The Core will electroporate totipotent ES cells with tar4getinbg vectors, select ES cell clones, and provide Center Members with DNA from the clones for genetic screening. Production of ES Cell-Mouse Chimeras: ES cell clones carrying the desired genetic mutation will be microinjected into mouse blastocysts which are surgically transferred to foster mothers to produce chimeras. Transgenic Technology Training: Researchers can also elect to be trained to 1) produce transgenic mice by pronuclear microinjection, 2) manipulate ES cells and produce gene targeted ES cell clones, and 3) produce ES cell-mouse chimeras by blastocyst injection. Commensurate with Center Member usage in the last four years, we project annual demand for 20 orders for transgenic mice, 6 orders for production of gene targeted ES cells, and 20 orders for ES cell-mouse chimeras. Center members will receive a 35% discount on the recharge rate for these services. Forty percent of all work done in the last four years by the Transgenic Core was devoted to Center members.